TY  - JOUR
A1  - Piesche, Matthias
A1  - Roos, Jessica
A1  - Kühn, Benjamin
A1  - Fettel, Jasmin
A1  - Hellmuth, Nadine
A1  - Brat, Camilla
A1  - Maucher, Isabelle Viktoria
A1  - Awad, Omar
A1  - Matrone, Carmela
A1  - Steffensen, Simon Gabriel Comerma
A1  - Manolikakes, Georg
A1  - Heinicke, Ulrike
A1  - Zacharowski, Kai
A1  - Steinhilber, Dieter
A1  - Maier, Thorsten Jürgen
T1  - The emerging therapeutic potential of nitro fatty acids and other Michael acceptor-containing drugs for the treatment of inflammation and cancer
T2  - Frontiers in pharmacology
N2  - Nitro fatty acids (NFAs) are endogenously generated lipid mediators deriving from reactions of unsaturated electrophilic fatty acids with reactive nitrogen species. Furthermore, Mediterranean diets can be a source of NFA. These highly electrophilic fatty acids can undergo Michael addition reaction with cysteine residues, leading to post-translational modifications (PTM) of selected regulatory proteins. Such modifications are capable of changing target protein function during cell signaling or in biosynthetic pathways. NFA target proteins include the peroxisome proliferator-activated receptor γ (PPAR-γ), the pro-inflammatory and tumorigenic nuclear factor-κB (NF-κB) signaling pathway, the pro-inflammatory 5-lipoxygenases (5-LO) biosynthesis pathway as well as soluble epoxide hydrolase (sEH), which is essentially involved in the regulation of vascular tone. In several animal models of inflammation and cancer, the therapeutic efficacy of well-tolerated NFA has been demonstrated. This has already led to clinical phase II studies investigating possible therapeutic effects of NFA in subjects with pulmonary arterial hypertension. Albeit Michael acceptors feature a broad spectrum of bioactivity, they have for a rather long time been avoided as drug candidates owing to their presumed unselective reactivity and toxicity. However, targeted covalent modification of regulatory proteins by Michael acceptors became recognized as a promising approach to drug discovery with the recent FDA approvals of the cancer therapeutics, afatanib (2013), ibrutinib (2013), and osimertinib (2015). Furthermore, the Michael acceptor, neratinib, a dual inhibitor of the human epidermal growth factor receptor 2 and epidermal growth factor receptor, was recently approved by the FDA (2017) and by the EMA (2018) for the treatment of breast cancer. Finally, a number of further Michael acceptor drug candidates are currently under clinical investigation for pharmacotherapy of inflammation and cancer. In this review, we focus on the pharmacology of NFA and other Michael acceptor drugs, summarizing their potential as an emerging class of future antiphlogistics and adjuvant in tumor therapeutics.
KW  - covalent drugs
KW  - electrophilic fatty acids
KW  - Michael acceptor
KW  - nitroalkylation
KW  - post-translational modifications
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/56129
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-561296
SN  - 1663-9812
N1  - This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
VL  - 11
IS  - art. 1297
SP  - 1
EP  - 16
PB  - Frontiers
CY  - Lausanne
ER  -